1. Field of the Invention
This application is a 371 of PCT/EP96/00381 filed on Feb. 2, 1996. The present invention relates to the use of carotenoids for producing drugs for the treatment of inflammatory disorders not caused by an infection with microorganisms or by the action of light, in particular abacterial, non-photoinduced dermatoses.
Inflammatory disorders for the purpose of this invention may be either allergic or non-allergic in nature, but the inflammatory reaction of the affected tissue is not caused by an infection with microorganisms and is not induced by the action of light.
Examples of appropriate disorders are:
pollinosis (seasonal rhinitis) PA1 perennial rhinitis PA1 polyposis nasi PA1 inflammatory disorders of the gastrointestinal tract such as regional enterocolitis (Crohn's disease), ulcerative colitis, irritable colon PA1 dermatoses, for example contact urticaria, urticaria pigmentosa PA1 allergic vasculitis PA1 insect allergy PA1 bronchial asthma PA1 allergic reactions of the outer eye PA1 allergic and pseudoallergic reactions to drugs PA1 systemic mastocytosis PA1 autoimmune disorders, for example systemic lupus erythematosus Sjogren's syndrome, thyreoditis, sic!, insulitis, glomerulonephritis.
Non-photoinduced, abacterial inflammatory dermatoses are in particular cutaneous vascular forms of allergy such as neurodermatitis or urticaria or else hyperkeratoses such as psoriasis.
It is highly probable that reactive oxygen species or singlet oxygen play an important part in the pathogenesis of various allergic and non-allergic inflammations. There is also suspected to be involvement of such species in degranulation with release of mediators from mast cells. It is certain that degranulation of mast cells and of basophilic granulocytes in blood represents the first step in the initiation of an allergic reaction.
One of the principal mediators of allergic reactions is histamine, and inhibition of its release or effect represents an important principle for the therapy of allergic inflammatory disorders.
2. Description of Related Art
Recent investigations have shown that histamine is released to considerable degrees not only in mast cells but also in human monocytes (G. Zwadlo-Klarwasser et al., Agent Actions 41, Special Conf. Issue: C99-C100, (1994)).
To date, glucocorticoids and H.sub.1 antagonists for example have mainly been used for the treatment of allergic dermatoses disorders, the latter being suitable only for systemic use.
Used for the treatment of bronchial asthma are, besides bronchiospasmolytics, cromones or steroid therapeutic agents. Usually employed for autoimmune disorders are steroids or else immunosuppressants.
The use of retinol (vitamin A) and retinoic acid derivatives is known for the treatment of some inflammatory dermatoses. Thus, retinol has been used for the treatment of juvenile acne and of psoriasis, although the suitability of this therapy proved to be low because of the overdosage manifestations.
The retinoids isotretinoin and etretinate are also suitable in principle for the treatment of acne and inflammatory hyperkeratoses such as psoriasis, but, like retinol, they easily give rise to symptoms of overdosage. In addition, etretinate is to be categorized as very problematic because of its highly teratogenic effect.
(cf. "W. Forth (editor), Pharmakologie und Toxikologie, page 404-5, 4th Edition, BI Wissenschaftsverlag, Mannheim).
It has also been found that the retinoids isotretinoin and etretinate are able to inhibit histamine release in human mast cells (D. Eichelberg and W. Schmutzler, Arch. Dermatol. Res., 280, 155-157 (1988)). However, because of the side effects which have already been mentioned, these agents are not recommended unconditionally for therapeutic use.
It is furthermore known that carotenoids such as .beta.-carotene (provitamin A) or canthaxanthin have been used for the treatment of light-induced dermatoses such as erythropoietic protoporphyria and urticaria solaris, and of dyschromias (vitiligo) (A. Hollander, "Neues aus der amerikanischen Dermatologie", Der Hautarzt, (1971) pp. 379-383). However, the therapeutic effect of carotenoids for urticaria solaris is regarded as uncertain (F. Lawlor et al., Z. Hautkrankh., 65, 17-27 (1989); A. Taaffe, Postgrad. Med. J., 53, 732-736 (1977).
To date there is no verified therapy for the treatment of allergic inflammatory neurodermatitis.